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Concentration Controlled Everolimus With Reduced Dose Cyclosporine Versus Mycophenolate Mofetil With Standard Dose Cyclosporine in de Novo Renal Transplant Adult Recipients Treated With Basiliximab and Corticosteroids

13 mai 2013 mis à jour par: Novartis

A 12-month, Multicenter, Randomized, Open-label Study to Investigate Efficacy and Safety of Concentration Controlled Everolimus With Reduced Dose Cyclosporine A Versus Mycophenolate Mofetil With Standard Dose Cyclosporine A in de Novo Renal Transplant Adult Recipients Treated With Basiliximab and Corticosteroids

The 12 Month Core Study (CRAD001A1202) was designed to evaluate the efficacy and safety comparing concentration-controlled everolimus (1.5 mg/day starting dose) with reduced dose cyclosporine and corticosteroids versus 2 g/day mycophenolate mofetil (MMF) with standard dose cyclosporine and corticosteroids in de novo renal transplant recipients.

Extension Study (CRAD001A1202E1): Until 24 months after renal transplantation, the study was designed to evaluate the long-term safety and efficacy comparing concentration-controlled everolimus with reduced dose cyclosporine (Neoral®) and corticosteroids versus mycophenolate mofetil with standard dose Neoral® and corticosteroids in de novo renal transplant recipients. Beyond 24 months after renal transplantation, the study was designed to provide everolimus treatment for patients in everolimus group until everolimus is approved and marketed in Japan.

Aperçu de l'étude

Type d'étude

Interventionnel

Inscription (Réel)

122

Phase

  • Phase 3

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

      • Tokyo, Japon, 106-8618
        • Novartis Pharma K.K., Japan

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans à 65 ans (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Core Study Inclusion Criteria:

  • Male or female de novo renal transplant recipients between 18 and 65 years of age
  • Patients who are receiving a primary cadaveric donor or non-human leukocyte antigen (non-HLA) identical living donor kidney transplant
  • Patients who have given written informed consent to participate in the study
  • Females capable of becoming pregnant must have a negative pregnancy test prior to randomization.

Core Study Exclusion Criteria:

  • Patients with no evidence of graft function within 24 hours of transplantation are excluded
  • Recipients of dual kidney transplants
  • Patients who are recipients of multiple solid organ or tissue transplants, or have previously received an organ or tissue transplant.
  • Recipients of kidneys from HLA-identical living related donors
  • Patients who are recipients of ABO incompatible transplants or T cell cross match positive transplant. Although Panel Reactive Antibodies (PRA) test is not mandatory, patients whose most recent anti-HLA Class I PRA >20% By a CDC-(Complement dependent cytotoxicity) based assay or >50% by a Flow Cytometry or ELISA (Enzyme linked immunosorbent assay) -based assay
  • Patients who have tested positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B surface antigen. Laboratory results obtained within 6 months prior to randomization are acceptable, otherwise these tests should be performed within two weeks prior to randomization.
  • Recipients of organs from donors who test positive for Hepatitis B surface antigen, HCV or HIV are excluded
  • Donor organ with a cold ischemia time >24 hours
  • Donor age greater than 65 years
  • Patients with platelet count <100,000/mm at baseline before transplantation
  • Patients with an absolute neutrophil count of < 1,500/mm³ or white blood cell count of < 4,500/mm³ at baseline before transplantation
  • Patients who have severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >8.5 mmol/L). Patients with controlled hyperlipidemia are acceptable
  • Patients who have an abnormal liver profile such as alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase (ALP) or total bilirubin >3 times the upper limit of normal (ULN)
  • Patients with a known hypersensitivity to either of the study drugs or their class, or to any of the excipients
  • Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450
  • Patients who are unable to take oral medication at time of randomization
  • Patients who received an investigational drug or who have been treated with a non-protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to randomization
  • Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized excised non-melanomatous skin lesions
  • Patients with clinically significant systemic infection at time of transplant or within two weeks prior to transplant
  • Patients with a history of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus
  • Patients who have cardiac failure at time of screening (resting dyspnea, with Grade ≥ 3 according to Old New York Heart Association Classification (Appendix 7) or any severe cardiac disease as determined by the investigator
  • Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study medication
  • Patients with abnormal physical or laboratory findings of clinical significance within 2 weeks prior to randomization which would interfere with the objectives of the study
  • Patients with any history of coagulopathy or medical condition requiring long-term anticoagulation which would preclude renal biopsy after transplantation. (Low dose aspirin treatment or interruption of chronic anticoagulant is allowed)
  • Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception.

Extension Study Inclusion Criteria:

  • Patients who completed Month 12 visit in core study (including patients who had discontinued study medication)
  • Patients who had given written informed consent to participate in this extension study

Extension Study Exclusion Criteria:

  • Women of childbearing potential who were planning to become pregnant, who were unwilling to use two or more effective means of contraception, including abstinence judged by the investigator, surgical sterilization (e.g. bilateral tubal ligation, hysterectomy), hormonal contraception (implantable, patch, oral), and barrier methods (male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception.

Other protocol-defined inclusion/exclusion criteria may apply

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: La prévention
  • Répartition: Randomisé
  • Modèle interventionnel: Affectation parallèle
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: Everolimus + Reduced dose of cyclosporine
An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg/day) was administered 24-36 hours from reperfusion after transplantation and dose adjustments based on everolimus trough level (target trough level 3-8 ng/mL). Reduced dose of cyclosporine was initiated either pre-transplantation or within 24 hours after transplantation following the local regimen. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study. Everolimus was available after 24 months for compassionate use.
0.75 mg twice daily, trough level adjusting between 3 and 8 ng/ml.
Autres noms:
  • Certican
Patients received first dose of basiliximab (20 mg) 2 hours prior to transplantation and 20 mg at Day 4 or according to local practice
The cyclosporine was initiated either pre-transplant or within 24 hours after transplantation following local regime. Standard dose of cyclosporine was administered with MMF. The Reduced dose of cyclosporine was administered with everolimus.
Autres noms:
  • Néoral®
Corticosteroid was administered according to local practice during the trial but at a dose not less than 5mg per day for 12 months of the study
Comparateur actif: Mycophenolate mofetil (MMF) + Standard dose of cyclosporine
Patients were treated with 1 gram twice a day (2 grams/day) of Mycophenolate mofetil (MMF) and standard dose of cyclosporine for 12 months post renal transplant. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study.
Patients received first dose of basiliximab (20 mg) 2 hours prior to transplantation and 20 mg at Day 4 or according to local practice
The cyclosporine was initiated either pre-transplant or within 24 hours after transplantation following local regime. Standard dose of cyclosporine was administered with MMF. The Reduced dose of cyclosporine was administered with everolimus.
Autres noms:
  • Néoral®
Corticosteroid was administered according to local practice during the trial but at a dose not less than 5mg per day for 12 months of the study
The initial dose of 2 gm/day Mycophenolate mofetil was started within 24-36 hours from reperfusion after transplantation. MMF was administered daily for 12 months in the core study and 12 months in the extension study.
Autres noms:
  • MMF

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Core Study: Number of Patients With Composite Efficacy Endpoint
Délai: 12 months

The composite efficacy endpoint consisted of treated biopsy proven acute rejection (BPAR) episodes, graft loss, death or loss to follow-up. A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. The allograft was presumed to be lost on the day the patient starts dialysis and was not able to stop dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.

For the individual components (including loss of follow-up)of the composite endpoint, patients are counted for the first event to occur.

12 months
Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using the Modification of Diet in Renal Disease (MDRD) Formula
Délai: Month 24

Renal function was assessed by glomerular filtration rate (GFR) using the MDRD formula:

GFR [mL/min/1.73m2] = 186.3*(C-1.154)*(A-0.203)*G*R C is the serum concentration of creatinine [mg/dL] A is age [years] G = 0.742 when gender is female, otherwise G=1 R = 1.21 when race is black, otherwise R=1

Loss to follow up (in In Primary Core Outcome Measure) is composite efficacy failure and contains incidence of treated BPAR, graft loss, death or loss to follow-up

Month 24
Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using the Modification of Diet in Renal Disease (MDRD) Formula
Délai: Month 48

Renal function was assessed by glomerular filtration rate (GFR) using the MDRD formula:

GFR [mL/min/1.73m2] = 186.3*(C-1.154)*(A-0.203)*G*R C is the serum concentration of creatinine [mg/dL] A is age [years] G = 0.742 when gender is female, otherwise G=1 R = 1.21 when race is black, otherwise R=1

Month 48

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Core Study: Number Participants With Combined Graft Loss, Death or Loss to Follow-up
Délai: 12 months

The allograft was presumed to be lost on the day the patient starts dialysis and was not able to stop dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.

A loss to follow-up in graft loss, death or loss to follow-up is a patient who did not experience graft loss or death and whose last day of contact was prior to Day 316, i.e. prior to the Month 12 visit window.

12 months
Core Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula
Délai: Month 12

Modification of Diet in Renal Disease (MDRD) formula is:

Calculated GFR [mL/min/1.73m^2] = 186.3*(C^-1.154)*(A^-0.203)*G*R where

  • C is the serum concentration of creatinine [mg/dL],
  • A is patient age at sample collection date [years],
  • G=0.742 when gender is female, otherwise G=1,
  • R=1.21 when race is black, otherwise R=1
Month 12
Extension Study: Number of Participants With Combined Efficacy Endpoint: Graft Loss, Death, Loss to Follow-up and/or Treated Biopsy Proven Acute Rejection (BPAR)
Délai: 24 Months

Graft loss was defined as the day the patient started dialysis and was not able to subsequently be removed from dialysis or re-transplant.

Loss-to-follow was a patient who did not experience a treated BPAR, graft loss or death and whose last day of contact was prior to Month 24.

A Graft Biopsy was done within 48 hours of suspect rejection. Biopsies were read by the local pathologist according to the updated Banff '97 criteria.

Treated BPAR was based on local laboratory biopsy results and was defined as a biopsy Banff criteria graded IA to III that was treated with anti-rejection therapy.

24 Months
Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (GFR) Using the Nankivell Formula
Délai: Month 24, Month 48

The Nankivell formula was used to calculate GFR at Month 24:

GFR[mL/min]=6.7/C + W/4 - UREA/2 - 100/H^2 + 35 (25 for females) W= body weight [kg] H= height [m] C= serum creatinine [mmol/L] UREA= serum urea [mmol\L]

Month 24, Month 48
Extension Study: Number of Participants With Adverse Events and Serious Adverse Events
Délai: 24 Months
Additional information about Adverse Events can be found in the Adverse Event Section.
24 Months
Extension Study: Everolimus Trough Levels
Délai: Month 24, Month 48
Blood was collected at all visits after Day 3 for trough (collected 5 minutes before study drug dose) everolimus levels and was analyzed at a central laboratory using liquid chromatography mass spectrometry.
Month 24, Month 48
Extension Study: Cyclosporine Trough Levels
Délai: Month 24, Month 48
Blood was collected at all visits after Day 3 for trough (collected 5 minutes before study drug dose) cyclosporine levels and was analyzed at a central laboratory using immunoassay.
Month 24, Month 48

Collaborateurs et enquêteurs

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Publications et liens utiles

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Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 février 2008

Achèvement primaire (Réel)

1 août 2010

Achèvement de l'étude (Réel)

1 mai 2012

Dates d'inscription aux études

Première soumission

10 avril 2008

Première soumission répondant aux critères de contrôle qualité

14 avril 2008

Première publication (Estimation)

15 avril 2008

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

21 juin 2013

Dernière mise à jour soumise répondant aux critères de contrôle qualité

13 mai 2013

Dernière vérification

1 mai 2013

Plus d'information

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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